A MECHANISM FOR THE MAJOR HISTOCOMPATIBILITY COMPLEX-LINKED RESISTANCE TO AUTOIMMUNITY

Certain major histocompatibility complex (MHC) class II haplotypes enc ode elements providing either susceptibility or dominant resistance to the development of spontaneous autoimmune diseases via mechanisms tha t remain undefined. Here we show that a pancreatic beta cell-reactive, I-A(g7)-restricted, transgenic TCR that is highly diabetogenic in non obese diabetic mice (H-2(g7)) undergoes thymocyte negative selection i n diabetes-resistant H-2(g7/b), H-2(g7/k), H-2(g7/q), and H-2(g7/nb1) NOD mice by engaging antidiabetogenic MHC class II molecules on thymic bone marrow-derived cells, independently of endogenous superantigens. Thymocyte deletion is complete in the presence of I-A(b), I-A(k) + I- E-k or I-A(nb1) + I-E-nb1 molecules, partial in the presence of I-A(q) or I-A(k) molecules alone, and absent in the presence of I-A(s) molec ules. Mice that delete the transgenic TCR develop variable degrees of insulitis that correlate with the extent of thymocyte deletion, but ar e invariably resistant to diabetes development. These results provide an explanation as to how protective MHC class II genes carried on one haplotype can override the genetic susceptibility to an autoimmune dis ease provided by allelic MHC class II genes carried on a second haplot ype.